Alzheimer brain shows two types of insoluble material: the extracellular amyloid protein and the intracellular neurofibrillary tangles formed from tau protein. Although most studies to date have focused on tau tangle synthesis, we hypothesize that tau accumulation results from failures in the cellular protein degradation machinery. Far from being a passive phenomenon, protein degradation requires a significant expenditure of energy, and is regulated with a very high degree of specificity to rid the cell of toxic proteins. Support for our hypothesis comes from other neurodegenerative conditions such as spinocerebellar degeneration, in which emerging evidence suggests that protein degradation pathways play key roles in disease pathologies, just as they are of central importance in cell homeostasis. However, the mechanisms of these degradative defects, and their roles in the disease cascade are unknown. An in-depth examination of this facet of neurofibrillary pathology is required. Specific aims: 1) Determine how changes in the levels of chaperone proteins (such as BiP) involved in the stress response affect tau production, degradation, and tangle formation in neurons. 2) Determine whether tau production, degradation, and tangle formation induces stress response pathways in neurons. 3) Measure how phosphorylation (and dephosphorylation) of tau affects its production, degradation, and tangle formation. This study may need to be carried out in yeast, as the technology to perform these measurements in neurons is not yet available. 4) Develop a comprehensive mechanistic model of tau cellular pathways, integrating all of these competing cellular processes. Perform a computational simulation and a sensitivity analysis of the tau pathways to identify the keys steps in tau tangle formation. The long-term goals of our overall project and new collaboration are to: Define biochemical and cellular pathways of tau homeostasis, focusing on degradation pathways, tangle formation, and long-term stress response leading to apoptosis. Identify steps in the tau pathways that are good targets for therapeutic intervention. [unreadable] [unreadable] [unreadable]